DESCRIPTION: Visceral leishmaniasis (VL) is caused by the obligate intracellular parasites Leishmania donovani (L. donovani) or L. chagasi and is a life-threatening neglected tropical disease of global health concern. We present a method for the treatment of drug resistant L. donovani using both a chemotherapeutic specific for the pathogen (Amphotericin B (Amp)), and an adjuvant that increases the immune response against the pathogen (resiquimod (R-848)). We hypothesize that treating with Amp and R-848 will synergistically treat drug resistant L. donovani. Amp is a chemotherapeutic that works directly on the parasite, while R-848 is an adjuvant that activates infected macrophages that allows for the clearance of intracellular parasites. Prior research has shown that imidazoquinolines with parasite specific chemotherapies synergize in the clearance of cutaneous leishmaniasis. Since we can formulate both R-848 and Amp into Acetated Dextran (Ace-DEX) microparticles (MPs) that can potentially target tissues where infected macrophages reside, we will use these microparticles as a platform to treat VL. This grant is innovative for the following reasons: 1.) Co- encapsulation of both a host-targeted adjuvant and an antiparasitic drug could synergistically treat the infection as well as other lethal infections; 2.) Ability to treat drug resistant parasites. 3.) Ace-DEX MPs can release encapsulated cargo inside the macrophage phagosome which allows for drug targeting inside the infected cell; 4.) Ace-DEX polymer has pH neutral degradation products, unique from conventional biomaterials; 5.) Ace-DEX polymer has tunable degradation kinetics that can range from hours to months allowing for the continuous release of encapsulated drugs; 6.) Previous research has shown that encapsulation in Ace- DEX has resulted in dose sparing of compounds; 7.) Ace-DEX encapsulation offers protection of encapsulates when stored outside the cold chain. In order to test our hypothesis we propose the following two specific aims. Specific Aim 1 involves the co-encapsulation of R-848 with Amp in Ace-DEX MPs (R- 848/Amp/MPs). Specific Aim 2 focuses on the biodistribution of MPs and the subsequent treatment of infected hamsters with susceptible or Amp resistant strains of L. donovani. Initially we will develop a particle that has optimal targeting of the bone marrow, liver and spleen. If successful, the concept of delivering a chemotherapeutic with an adjuvant could be applied to other pathogenic infections.